The most common genetic entity in childhood acute lymphoblastic leukemia (ALL) is associated with a t(12;21) chromosomal translocation that leads to expression of the fusion protein TEL-AMLl/runx1 from the TEL locus. Epidemic logical studies demonstrate that the TEL-AML1 fusion is present as a somatic mutation in newborns at a frequency at least 10-fold higher than the incidence of ALL. Hence, it is believed that additional events are required, including loss of function of the other TEL allele (as occurs in the vast majority of TEL-AML1 ALL). Current therapy of childhood ALL, though effective, is empirical and potentially toxic. Drug therapy targeted to genetic lesions in ALL offers the possibility of reducing morbidity while retaining efficacy. In order to approach this, a valid preclinical model of ALL is required. The goal here is to generate a model of TEL-AML1 leukemia in the mouse that accurately reflects the pathogenetics in man. We have generated conditional mutant mouse strains that permit activation of the TEL-AML1 fusion gene from the endogenous TEL locus (hence, at an appropriate expression level) and inactivation of TEL function either during embryogenesis or later in life. Activation of TEL-AML1 expression leads to a block in lymphopoiesis, expansion of a c-kit+ progenitor population, but no progression to frank leukemia. Thus, expression of the fusion protein from the endogenous TEL locus interferes with normal lymphoid development and appears to generate a "preleukemic" state. Our current aims (1) characterize further the preleukemic phenotype and the properties of the expanded c-kit+ population in TEL-AML1 expressing mice; (2) determine the phenotype of mice in which TEL-AML1 expression is activated later in hematopoiesis, specifically within the B-lymphoid lineage by intercrosses of flox-stopped TEL-AML1 mice with CD2-cre mice;(3) perform retroviral insertional mutagenesis in mice from (1) and (2) in order to convert preleukemia to leukemia and identify in vivo complementing genes;and (4) functionally test candidate tyrosine kinases identified in the Project 1 to complement mice in (I) and (2) and generate frank leukemia following retroviral gene transfer. These studies should lead to generation of mice that accurately model childhood ALL.